Overview of alopecia areata for managed care and payer stakeholders in the United States

Alopecia areata (AA) is an autoimmune disease with a complex pathophysiology resulting in nonscarring hair loss in genetically susceptible individuals. We aim to provide health care decision makers an overview of the pathophysiology of AA, its causes and diagnosis, disease burden, costs, comorbidities, and information on current and emerging treatment options to help inform payer benefit design and prior authorization decisions. Literature searches for AA were conducted using PubMed between 2016 and 2022 inclusive, using search terms covering the causes and diagnosis of AA, pathophysiology, comorbidities, disease management, costs, and impact on quality of life (QoL). AA is a polygenic autoimmune disease that significantly impacts QoL. Patients with AA face economic burden and an increased prevalence of psychiatric disease, as well as numerous systemic comorbidities. AA is predominantly treated using corticosteroids, systemic immunosuppressants, and topical immunotherapy. Currently, there are limited data to reliably inform effective treatment decisions, particularly for patients with extensive disease. However, several novel therapies that specifically target the immunopathology of AA have emerged, including Janus kinase (JAK) 1/2 inhibitors such as baricitinib and deuruxolitinib, and the JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinase inhibitor ritlecitinib. To support disease management, a disease severity classification tool, the Alopecia Areata Severity Scale, was recently developed that evaluates patients with AA holistically (extent of hair loss and other factors). AA is an autoimmune disease often associated with comorbidities and poor QoL, which poses a significant economic burden for payers and patients. Better treatments are needed for patients, and JAK inhibitors, among other approaches, may address this tremendous unmet medical need.

AA is a polygenic autoimmune disease that significantly impacts QoL. Patients with AA face economic burden and an increased prevalence of psychiatric disease, as well as numerous systemic comorbidities. AA is predominantly treated using corticosteroids, systemic immunosuppressants, and topical immunotherapy. Currently, there are limited data to reliably inform effective treatment decisions, particularly for patients with extensive disease. However, several novel therapies that specifically target the immunopathology of AA have emerged, including Janus kinase (JAK) 1/2 inhibitors such as baricitinib and deuruxolitinib, and the JAK3/ tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinase inhibitor ritlecitinib. To support disease management, a disease severity classification tool, the Alopecia Areata Severity Scale, was recently developed that evaluates patients with AA holistically (extent of hair loss and other factors).
AA is an autoimmune disease often associated with comorbidities and poor QoL, which poses a significant economic burden for payers and patients. Better treatments are needed for patients, and JAK inhibitors, among other approaches, may address this tremendous unmet medical need.

Plain language summary
Alopecia areata (AA) causes hair loss that can be hard to treat. It can impact the quality of life for adults and children and lead to poor attendance and performance at work or school. People with AA often have related health issues, and costs due to AA can be large. One treatment for AA is now approved for adults in the United States, and others have been shown to work in clinical studies.

Implications for managed care pharmacy
AA is an autoimmune disease often associated with other comorbidities and poor quality of life and poses an economic burden for payers and patients. The significant unmet medical need in the treatment of AA may be addressed by safe and effective therapeutic options that target the pathophysiology of disease. Decision makers, payers, and disease experts should carefully determine the best way of identifying appropriate patients for new treatments entering the marketplace.

Prevalence, Incidence, Natural History, and Clinical Spectrum of AA
The most common nonscarring (ie, the hair follicle is preserved, allowing for hair regrowth) hair loss disease is androgenetic alopecia, which, as the name implies, is often an androgen hormone-dependent form of alopecia and affects up to 80% of men and 50% of women in their lifetime. 8 Telogen effluvium is another form of nonscarring alopecia that results from profound biological stress (e.g., COVID-19 infection) and usually resolves spontaneously. Central centrifugal cicatricial alopecia is a scarring alopecia that typically presents as a patch of hair loss on the crown that enlarges over time. Although most often seen in women of African descent, it may occur in men and women of all races.
AA is the second most common form of alopecia and affects people of all ages, races, and sexes, 9 with male and female persons similarly affected. 2,10 Most patients experience disease onset by age 40, with a mean age of onset ranging from 25-36 years. 2,10 The National Alopecia Areata Foundation Registry (n = 2218) reports a mean age of onset in children of 5.9±4.1 years. 11 A random-effects meta-analysis suggested global prevalence is significantly lower in adults (1.47% [1.18-1.80]) than in children (1.92% [1.31-2.65]; P < 0.0001). 12 AA is usually a relapsing and remitting disease in which patches of hair loss occur unpredictably and resolve spontaneously, followed by variable periods of remission. However, typically in patients with more extensive hair loss, disease is persistent. The lifetime incidence of AA is 2%, 2 and an estimated 8.2 million people in the United States have had AA. 9 A cross-sectional US survey reported point prevalence of AA by disease severity. Point prevalence was 0.21% (95% CI = 0.17%-0.25%) overall; 0.12% (95% CI = 0.09%-0.15%) for mild disease (defined in the study as Severity of Alopecia Tool [SALT] score ≤ 50 [vida infra], indicating ≤ 50% scalp-hair loss); and 0.09% (95% CI = 0.06%-0.11%) for moderate to severe disease (SALT score > 50). 9 Point prevalence for the most extensive scalphair loss (alopecia totalis [AT] and alopecia universalis [AU], SALT score of 100 or complete scalp with or without body hair loss) was 0.04% (95% CI = 0.02%-0.06%). The data suggest that approximately 700,000 people currently live with AA in the United States, including approximately 300,000 with a SALT score of > 50, of whom up to half may have AT or AU. 9 Alopecia areata (AA) is an autoimmune 1 disease with a lifetime incidence of approximately 2%. 2 It is a T-cell-mediated nonscarring form of hair loss of the scalp, face, and/or body, with an underlying immunoinflammatory pathogenesis. 3 Comorbid autoimmune diseases are common in AA. The course of disease is often unpredictable, with periods of relapse and remission, though severe disease is usually chronic. Treatment for AA differs from other forms of hair loss.
Currently, the Janus kinase (JAK)1/2 inhibitor baricitinib is the only approved therapy (in some countries) for the treatment of severe AA. 4 Off-label treatments have limited tolerability and effectiveness. Frequent comorbidities and the psychosocial impact on patients contribute to the significant health care resource utilization (HCRU) and costs associated with AA. [5][6][7] The objective of this narrative review is to provide an overview of AA, including the genetic and autoimmune pathobiology, its differentiation from other forms of hair loss, common comorbidities, and treatment options. We also discuss the clinical, economic, and social burden of disease and the methods used to assess AA severity, which may be important to identify appropriate patients for treatment.

Literature Database Search Methods and Study Selection
Relevant studies were identified by an electronic literature search using the MEDLINE PubMed database between 2016 and 2021, inclusive, with a repeat search performed in January 2023 for any new publications. Searches included the following terms: alopecia areata AND (totalis OR universalis), (treat* OR therap*), ( , (patient reported OR patient-reported), incidence, prevalence, economic* OR cost* OR (direct cost*) OR (indirect cost*) OR (healthcare cost*), ([unmet need*] OR need*). The title and abstract of identified citations were screened for potential eligibility. Articles published prior to 2016 that were considered by the authors to be particularly relevant were also included.

Comorbidities
Comorbid autoimmune and inflammatory diseases in patients with AA are common, and shared genetics and immune pathways may be involved. 24,25 Multiple genes associated with AA are also linked with other autoimmune diseases, and associations between these diseases and AA have been found. [25][26][27][28][29][30][31][32][33][34][35][36] The interplay between AA and comorbid psychiatric disorders is complex, with contributions from genetic and environmental factors. 37 One large population-based retrospective cohort study reported that patients with AA have a 34% greater risk of developing major depressive disorder than the general population and that having major depressive disorder was a risk factor for the development of AA. 38 Additional studies have found an increased prevalence of anxiety and depression in patients with AA. 39-43

Impact of AA on Patient Quality of Life
AA can have a profoundly negative impact on health-related quality of life (HRQoL). 10,44 It can affect self-perception/ self-esteem, mental health/well-being, and relationships ( Figure 1). [45][46][47] Many patients describe a negative impact of AA on their professional life, having to take time off from work and having poor performance because of stress and lack of confidence due to AA. 48,49 For children and adolescents with AA, the condition can result in missing school, performing poorly, and even discontinuing education; increased rates of bullying are reported in children and adolescents with AA. 48,[50][51][52] Several studies have shown that AA can have a profound impact on HRQoL that is similar to or worse than that of other dermatological diseases, including atopic dermatitis and psoriasis 53,54 ( Figure 2). AA also affects the HRQoL of spouses/partners and families of patients (Supplementary Figure 1). 53,55 However, with successful treatment, patients with AA experience a positive impact on HRQoL. 56

Economic Burden of AA
In addition to a significant psychosocial burden, AA presents an economic burden to patients. In a cross-sectional, quantitative-qualitative survey in patients with self-reported AA, respondents reported seeing a range of health care professionals for disease management, including dermatologists (89%), primary care physicians (61%), and psychological

Diagnosis of AA and Disease Severity
Diagnosis of AA is usually based on clinical observation. A positive hair pull test or trichoscopy may be helpful in diagnosing AA 13 ; rarely, histopathology is necessary to confirm the diagnosis. 14 In addition to hair loss, up to 44% of patients present with nail abnormalities, often in more extensive cases of AA. 15 The most common AA subtypes include (1) patchy AA, the most common form, characterized by round/oval patches of hair loss on the scalp or other parts of the body; (2) ophiasis AA, hair loss involving the posterior hairline and extending to above the ears; (3) AT, complete loss of scalp hair; and (4) AU, complete loss of scalp, face, and body hair. 16 However, these classifications do not fully assess severity and are inadequate as they poorly characterize the clinical spectrum of disease and do not correlate with prognosis, 17 and definitions of AT and AU vary widely. 18 Clinically meaningful tools for assessing disease severity in AA are important for clinical decision-making and clinical trials. The SALT is a validated instrument that assesses the amount of scalp-hair loss, with SALT scores ranging from 0 (no scalp-hair loss) to 100 (complete scalp-hair loss) 19 (Supplementary Table 1, available in online article); the SALT score is used in clinical trials but not in daily practice. Anchored in the SALT score, the Alopecia Areata Investigator Global Assessment 20 was developed to detail clinically meaningful categories of scalp-hair loss that reflect patients' and expert clinicians' perspectives and treatment expectations. The Alopecia Areata Scale was developed by expert consensus and is amenable for use in daily clinical practice. 21 It is the only tool that accounts for scalp-hair loss along with other important disease features, including involvement of other body locations (eg, eyebrows, eyelashes), treatment responsiveness, and the psychosocial impact of disease.

AA Genetics and Pathophysiology
AA is an autoimmune disease. 14 Therefore, in contrast to androgenetic alopecia, AA has an immunoinflammatory pathogenesis. Hair loss in AA results from immune privilege collapse 22 and CD8 + T-cell attack of hair follicles, mediated by interferon-γ, interleukin (IL)-15, and other cytokines, some of which signal through JAK proteins. 23 The hair follicle is not destroyed, and hair is able to regrow if the inflammatory process is suppressed.
of US$1,961 per year for counseling and/or therapy. In an analysis of 14,792 adults with AA and 44,916 controls, mean total all-cause medical and pharmacy costs were higher in patients with AA than in controls ($13,686 for non-AT/ AU group vs $9,336 for matched controls; $18,988 for AT/ AU group vs $11,030 for matched controls; P < 0.001 for both). 5 Patient out-of-pocket costs were also significantly higher for patients with AA than for controls. 5 These results align with the significantly greater HCRU and costs relative to matched controls in a large retrospective analysis of patients with AA and matched controls. 6 Significantly higher HCRU and all-cause costs have also been shown in adolescents with AA than in matched controls (total payer costs of $7,587 for non-AT/AU subgroup vs $4,496 for matched controls; $9,397 for AT/AU subgroup vs $2,267 for matched controls; P < 0.001 for both). 7 In a survey of 675 patients with AA, more than half reported moderate or serious financial burden of AA, with the greatest out-of-pocket costs being for headwear/cosmetic options, vitamins, supplements, or other treatments, as well as copays/out-of-pocket deductibles for doctor visits. 57 Another study highlighted a lack of medical insurance coverage for concealment strategies, with a mean cost of approximately $2,200 per year. 48 or behavioral health specialists (23%). 48 Almost half of the 216 respondents did not have US insurance coverage for treatment and described treatment costs up to a mean   methotrexate, or azathioprine, concurrent prednisolone was necessary in 58%, 64%, and 67% of patients, respectively, to achieve results meriting continued therapy after 12 months. 64

EMERGING THERAPIES
Recent advances in our understanding of AA pathogenesis have led to targeted therapy of this autoimmune disease. JAK inhibitors are being evaluated in large, randomized phase 2 and 3 trials in patients with AA with ≥ 50% scalp-hair loss; in these trials, approximately half of patients have complete scalp-hair loss, and many have eyebrow and eyelash loss. The JAK1/2 inhibitor baricitinib is approved for AA by the US Food and Drug Administration. 4 In the phase 3 BRAVE-AA1 trial (NCT03570749), 39% and 23% of patients receiving baricitinib 4 mg and 2 mg, respectively, had response based on SALT ≤ 20 at week 36 compared with 6% of patients receiving placebo (Supplementary Table 2). 65 Similar results were demonstrated in BRAVE-AA2 (NCT03899259). 65 The JAK3/TEC family kinase inhibitor ritlecitinib was evaluated in the ALLEGRO 2b/3 trial in patients aged 12 years and older and with ≥ 50% hair loss (NCT03732807): 31%, 22%, 23%, and 14% of patients receiving ritlecitinib 200/50 mg, 200/30 mg, 50 mg, and 30 mg, respectively, had response based on SALT ≤ 20 at week 24 compared with 2% of patients receiving placebo. 66 The JAK1/2 inhibitor deuruxolitinib (formerly CTP-543) was evaluated in the THRIVE-AA1 trial (NCT04518995): 42% and 30% of patients receiving deuruxolitinib 12 mg and 8 mg, respectively, had response based on SALT ≤ 20 at week 24 compared with 1% of patients receiving placebo. 67 Similar results were seen in the THRIVE-AA2 trial (NCT04797650). 68 Phase 3 trials of the JAK1/2/3 inhibitor jaktinib (NCT05051761) and the JAK1 inhibitor ivarmacitinib (NCT05470431) are ongoing.

LIMITATIONS
A broad literature search was undertaken to cover multiple aspects of AA for this review; however, relevant articles may have been excluded because of the search terms chosen.

Current and Emerging Treatment Options
The appropriate treatment for patients with AA should consider several factors, including the extent and location of scalp-hair loss, involvement of frontal hairline or mid-scalp, duration of AA, and psychosocial impact of disease. 58,59 In 2020, prior to the approval of a treatment for AA, the Alopecia Areata Consensus of Experts, a global network of dermatologists with recognized expertise in hair and scalp disorder management, commented that "robust treatment efficacy data for AA are limited." 58 It is therefore unsurprising that patients with AA are dissatisfied with traditional treatments. 60 In evidence of this, the National Alopecia Areata Foundation survey of more than 1,000 patients with AA reported that 78% were "very" or "somewhat unsatisfied" with their current medical treatments. 60 Regardless of treatment, relapse rates are high when patients with extensive AA discontinue treatment 61 ; therefore, maintenance therapy is usually necessary, although many therapies limit long-term use because of their adverse-effect profiles.

LIMITED HAIR LOSS (TOPICAL THERAPIES)
Corticosteroids (intralesional or topical) are often used as first-line therapy for limited scalp-hair loss. Although intralesional corticosteroids are the most effective treatment, patient age must be considered. 58,59 Treatment of 20% scalphair loss with intralesional corticosteroids may require 70 or more injections. Because this treatment is painful and may be needed monthly for a few or more months, it may be inappropriate in children and those with more extensive hair loss.
Topical immunotherapies, such as diphenylcyclopropenone or squaric acid dibutylester, cause allergic contact dermatitis, which leads to changes in the immune environment of hair follicles. 62 The goal of treatment is, in a sense, to cause itchy and red skin, and so topical immunotherapy is usually reserved for cases of limited scalp-hair loss. Diphenylcyclopropenone and squaric acid dibutylester are not commercially available, must be compounded, and are uncommon. 59

MODERATE TO SEVERE HAIR LOSS (SYSTEMIC THERAPIES)
High doses of systemic corticosteroids can be effective for more extensive hair loss, but relapse rates are high, and long-term use is associated with numerous adverse events. 63 Steroid-sparing immunosuppressants are rarely effective as monotherapy for the treatment of AA. In a retrospective study of 138 patients with AA receiving cyclosporine, Overview of alopecia areata for managed care and payer stakeholders in the United States Additionally, the lack of systematic review methodology may have resulted in potential bias in the articles chosen.

Summary
AA is an autoimmune disease that can affect genetically predisposed individuals. Patients with AA commonly experience other autoimmune comorbidities, 25,27,28 and disease can have a negative impact on HRQoL, resulting in poor attendance and performance at work or school. 48 The number of people in the United States living with AA with a SALT score > 50 is estimated at 300,000. 9 The significant unmet medical need of patients with AA 70 may be addressed by safe and effective treatment options that target the pathophysiology of disease.
Multiple emerging treatments are expected to soon be approved for the treatment of AA in adolescents and adults. Health care decision makers will need to determine their approach to evaluating AA treatments to provide care to their members with AA.